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Small Molecule Drug Shows Promise in Fighting Ebola, Marburg Infection in Primates

By BiotechDaily International staff writers
Posted on 19 Mar 2014
Image: Marburg virus (Photo courtesy of the CDC – US Centers for Disease Control).
Image: Marburg virus (Photo courtesy of the CDC – US Centers for Disease Control).
A new small molecule agent has been shown to be effective in extensive lab and nonclincial testing in fighting animal models of filovirus infection with Marburgvirus (MARV) and Ebolavirus (EBOV), two highly virulent pathogens responsible for viral hemorrhagic fever diseases.

The new findings of the broad-spectrum nucleoside analogue BCX4430 represents the first evidence of protection of nonhuman primates from filovirus disease by a small molecule drug, and reported the efficacy findings generated from an ongoing collaboration between scientists at the US Army Medical Research Institute of Infectious Diseases (USAMRIID; Frederick, MD, USA) and BioCryst Pharmaceuticals, Inc. (Durham, NC, USA).The study was published online March 2, 2014, in the journal Nature.

Filoviruses, such as EBOV and MARV, are extremely virulent. Case fatality rates tied to filovirus disease outbreaks are the highest reported for any infection, exceeding 90%. These pathogens are classified as Category A Bioterrorism Agents by the US Centers for Disease Control and Prevention (Atlanta, GA, USA). BCX4430 was found to totally protect cynomolgus macaques from MARV infection when given by intramuscular (IM) injection 48 hours postinfection. Postexposure intramuscular administration of the BCX4430 agent also protected rodents against MARV and EBOV infections. Furthermore, BCX4430 was shown to be active in vitro against a wide range of other RNA viruses, including the emerging viral pathogen Middle East respiratory syndrome coronavirus (MERS-CoV).

“Filoviruses, such as Ebola and MARV, constitute serious threats to our national defense,” said Colonel Erin P. Edgar, commander of USAMRIID. “Development of cost-effective and versatile treatment options to combat these agents remains an unmet medical need and a high biodefense priority for the US Government.”

Developed by BioCryst, BCX4430 has demonstrated antiviral activity in testing conducted at BioCryst, Utah State University/NIAID, and USAMRIID. BCX4430 has been shown to be active against more than 20 RNA viruses in nine different families, including filoviruses, togaviruses, bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. In tests conducted at USAMRIID, BCX4430 protected animals against parenteral exposures to MARV, EBOV, and Rift Valley Fever virus and from exposures to aerosolized MARV, an experimental condition designed to mimic an exposure situation that could result during a bioterrorist attack.

“With its broad-spectrum antiviral activity, attractive drug-like characteristics, and demonstrated efficacy against filoviruses, BCX4430 is well-positioned for continued development as a valuable addition to the nation’s arsenal of medical countermeasures,” said Dr. William P. Sheridan, chief medical officer at BioCryst. “A single broad-spectrum agent that treats a range of RNA virus threats, such as BCX4430, presents an efficient one-drug, multibug strategic option against high-priority pathogens for the US Government and offers promise as a treatment for patients infected in natural outbreaks.”

BCX4430 is being developed as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats. In September 2013, the US National Institute of Allergy and Infectious Diseases (NIAID; Bethesda, MD, USA) contracted with BioCryst for the development of BCX4430 as a treatment for MARV disease. In 2013, NIAID awarded funding of USD 7.5 million to BioCryst, and total funding of up to USD 22.0 million if all contract options are implemented. The goals of this contract are to file investigational new drug (IND) applications for intravenous and intramuscular BCX4430 for the treatment of MARV disease, and to conduct phase 1 human clinical trials.

The objective of BioCryst’s broad spectrum antiviral (BSAV) research program is to develop broad-spectrum parenteral and oral therapeutics for viruses that pose a threat to health and US National security. The lead BSAV compound is BCX4430, which acts by terminating viral RNA synthesis, has demonstrated broad-spectrum activity for multiple viruses and a favorable early preclinical safety profile. BCX4430 has protected animals against viral hemorrhagic fever infections in models of MARV, EBOV, and Yellow Fever virus. BioCryst is developing BCX4430 following the Animal Rule regulatory pathway.

MARV is a member of the family Filoviridae, along with Ravn virus, EBOV, Sudan virus and Bundibugyo virus, all of which cause severe viral hemorrhagic fevers in humans. Reported case fatality rates have been reported to exceed 90%.

BioCryst Pharmaceuticals designs and develops small molecule drugs that block key enzymes involved in infectious and rare diseases, with the objective of addressing unmet medical needs of patients and physicians. BioCryst’s key development programs include BCX4161 and two next-generation oral inhibitors of plasma kallikrein for hereditary angioedema; peramivir, a viral neuraminidase inhibitor for the treatment of influenza; and BCX4430, a broad-spectrum antiviral for hemorrhagic fevers.

Related Links:

BioCryst Pharmaceuticals
US Army Medical Research Institute of Infectious Diseases



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